Amyloid beta (Aβ) peptides, a major contributor to Alzheimers disease, occur in differing lengths, each of which forms a multitude of assembly types. The most toxic soluble oligomers are formed by Aβ42; some of which have antiparallel β-sheets. Previously, our group proposed molecular models of Aβ42 hexamers in which the C-terminus third of the peptide (S3) forms an antiparallel 6-stranded β-barrel that is surrounded by an antiparallel barrel formed by the more polar N-terminus (S1) and middle (S2) portions. These hexamers were proposed to act as seeds from which dodecamers, octadecamers, both smooth and beaded annular protofibrils, and transmembrane channels form. Since then, numerous aspects of our models have been supported by experimental findings. Recently, NMR-based structures have been proposed for Aβ42 tetramers and octamers, and NMR studies have been reported for oligomers composed of ~ 32 monomers. Here we propose a range of concentric β-barrel models and compare their dimensions to image-averaged electron micrographs of both beaded annular protofibrils (bAPFs) and smooth annular protofibrils (sAPFs) of Aβ42. The smaller oligomers have 6, 8, 12, 16, and 18 monomers. These beads string together to form necklace-like bAPFs. These gradually morph into sAPFs in which a S3 β-barrel is shielded on one or both sides by β-barrels formed from S1 and S2 segments.

Amyloid beta (Aβ of Alzheimer’s disease) and α-synuclein (α-Syn of Parkinson’s disease) form large fibrils. Evidence is increasing however that much smaller oligomers are more toxic and that these oligomers can form transmembrane ion channels. We have proposed previously that Aβ42 oligomers, annular protofibrils, and ion channels adopt concentric β-barrel molecular structures. Here we extend that hypothesis to the superfamily of α, β, and γ-synucleins. Our models of numerous Synuclein oligomers, annular protofibrils, tubular protofibrils, lipoproteins, and ion channels were developed to be consistent with sizes, shapes, molecular weights, and secondary structures of assemblies as determined by EM and other studies. The models have the following features: 1) all subunits have identical structures and interactions; 2) they are consistent with conventional β-barrel theory; 3) the distance between walls of adjacent β-barrels is between 0.6 and 1.2 nm; 4) hydrogen bonds, salt bridges, interactions among aromatic side-chains, burial and tight packing of hydrophobic side-chains, and aqueous solvent exposure of hydrophilic side-chains are relatively optimal; and 5) residues that are identical among distantly related homologous proteins cluster in the interior of most oligomers whereas residues that are hypervariable are exposed on protein surfaces. Atomic scale models of some assemblies were developed.